拔毒生肌散的毒性特点及方中炉甘石对汞毒性的影响研究
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摘要
应用红粉、轻粉、朱砂等含汞成分中药及其制剂治疗慢性难愈性皮肤溃疡是中医外科的特色之一。但因其含有汞、铅等重金属成分,加之没有明确的使用剂量和周期,存在较大的安全性隐患,使该类传统外用制剂的临床应用和推广受到了限制。本研究选择来源于古代外科名方“生肌散”的拔毒生肌散(Badu Shengji San,BDSJS)为代表药物,研究其毒性特点,以为临床安全用药提供基础研究数据。目前,国内对含汞外用制剂反复用药后的毒性特点尚无报道。
国外最新研究发现ZnCl2对HgCl2引起的乳鼠肾损伤具有保护作用。提示,锌对汞诱发的肾损伤具有一定的保护作用。本课题前期研究已证明汞是BDSJS的主要毒性成分,肾脏是其主要毒性靶器官,且方中的配伍药味能够减轻汞所致的肾损伤。在配伍药味中,炉甘石(煅)的主要成分是氧化锌。由此我们在前期研究基础上进行推论,认为以锌为主要成分的炉甘石可能是BDSJS中汞成分的减毒药味。基于以上认识,本研究以含汞成分的红粉作为染毒药物,观察炉甘石对破损皮肤大鼠肾损伤的影响,探讨其对汞代谢方面的可能影响及其机制。目前,国内对炉甘石及锌降低汞毒性及其配伍减毒机制尚无报道。
本论文包括两个部分：BDSJS的毒性特点和方中炉甘石对汞毒性的影响。
1BDSJS的毒性特点研究
1.1对破损皮肤大鼠反复给药汞成分在体内的蓄积情况研究
目的
观察BDSJS反复给药后汞成分在大鼠体内的蓄积情况,明确BDSJS的安全剂量、用药周期及毒性可逆程度。
方法
采用破损皮肤大鼠模型,分别以高、中、低剂量的100、50、25mg/kg BDSJS涂敷于大鼠背部破损皮肤给药区,敷药后固定24h,每日给药1次,连续给药4周。检测给药4周、停药4周及停药8周大鼠血、尿、肾皮质中的汞含量,观察汞成分在破损皮肤大鼠体内的蓄积情况,并以肾早期损伤指标尿视黄醇结合蛋白(RBP)、N-乙酰-p-D-氨基葡萄糖苷酶(NAG)和β2-微球蛋白(β2-MG)含量、肝肾功能、凝血时间及肾组织形态学变化为肾毒性指标,评价汞蓄积是否可造成肾组织的损伤及其严重程度。
结果
与破损皮肤对照组比较,用药4周BDSJS高、中、低剂量组大鼠的血汞、尿汞、肾汞含量均明显升高,且升高呈剂量依赖性；停药4周,BDSJS各组大鼠的血汞含量均已恢复至正常水平,尿汞含量下降80-90%,肾汞含量下降50%以上；停药8周, BDSJS各组大鼠尿汞均恢复至正常水平,肾汞下降70%以上,但仍有一定蓄积。
BDSJS高剂量组给药4周,在肾汞含量为(47.99±15.66)ng/g,血汞含量为(72.06±18.03)ng/g,尿汞含量为(1278.84±711.82)ng/mL时,大鼠出现肾脏系数和β2-MG含量的明显升高,肾组织病理检查见少数大鼠出现肾小管上皮细胞肿胀；停药4周,肾汞含量为(20.43±5.09)ng/g,尿汞含量为(82.70±25.83)ng/mL,血汞含量为(5.59±0.94)ng/mL(基本恢复正常水平)时,肾脏系数、尿P2-MG及肾组织形态基本恢复正常；停药8周,虽肾组织中汞仍有一定蓄积,含量为(18.60±12.35)ng/g,但尿β2-MG及肾组织形态恢复正常。中、低剂量组大鼠在给药4周,血汞分别为(38.44±28.72)ng/g和(26.63±18.67)ng/g,尿汞分别为(380.80±119.32) ng/mL和(239.53±110.34)ng/mL,肾汞含量分别为(31.27±11.21)μg/g和(11.93±3.12)μg/g,但肾脏系数及尿P2-MG未见明显差异。
结论
BDSJS连续外敷4周,可造成汞在破损皮肤大鼠血液及肾脏中的蓄积,主要蓄积在肾脏；血中汞的清除较快,停药4周基本恢复到正常水平；停药8周,BDSJS中、低剂量组大鼠尿汞恢复至正常水平,肾脏中汞的清除超过70%,但仍有一定蓄积；BDSJS高剂量100mg/kg可造成肾小管的轻度损伤,但其损伤是可逆的,停药4周后可基本恢复,中剂量50mg/kg为其安全剂量。
1.2BDSJS对慢性皮肤溃疡患者汞成分在机体内的蓄积情况研究
目的
采用动物安全性评价得出的安全剂量和用药周期,观察慢性下肢疮疡患者以BDSJS外敷治疗4周及停药后汞在体内的蓄积情况,为制定临床安全剂量和给药周期提供依据。
方法
入组患者每日给药1次,或视患者创面情况隔日换药1次,以0.28mg/cm2/d的剂量治疗4周,测定患者治疗前、治疗4周、停药2周及停药6周的血汞及尿汞含量,并以血清ALT、AST、BUN、Cr、尿NAG及β2-MG为毒性观察指标,评价汞蓄积对患者肝、肾功能指标的影响。
结果
外敷BDSJS治疗慢性皮肤溃疡,患者在用药4周血汞含量为(8.10±14.81)ng/mL,尿汞含量为(11.51±17.75)ng/mL,与治疗前比较,血汞含量有升高趋势,尿汞含量明显升高；停药2周和停药6周,患者血汞及尿汞含量未见明显升高。
与治疗前比较,治疗4周、停药2周及停药6周,血清中ALT、AST、BUN、Cr及尿β2-MG含量未见明显升高；治疗4周,患者尿NAG含量明显升高,停药2周,尿NAG含量有升高趋势,停药6周,尿NAG含量未见明显升高。
结论
慢性难愈性下肢溃疡患者20例,患处外敷BDSJS,以0.28mg/cm2/d剂量用药4周,在患者尿中检测到汞含量明显升高,血汞含量有升高趋势；停药6周,患者血汞及尿汞基本恢复至正常水平。但治疗期及停药期BDSJS均未造成肝肾功能的明显异常,提示,汞在机体内短时间蓄积(血汞含量低于8.1ng/mL,尿汞低于含量11.5ng/mL)不会导致肾损伤。该研究结果进一步证实,动物安全性实验得出的安全剂量和周期对临床用药具有指导作用。
1.3对不同皮肤损伤条件大鼠的肾毒性差异
目的
比较BDSJS对不同皮肤损伤条件大鼠的肾毒性差异。
方法
采用BDSJS的毒性剂量,以肾脏系数、尿RBP、NAG含量及肾组织的病理形态为肾毒性观察指标,比较其对破损皮肤和疮疡皮肤两种不同皮肤损伤条件大鼠的肾毒性差异。
结果
与破损皮肤对照组比较,破损皮肤+BDSJS240mg/kg组大鼠的尿NAG、RBP含量明显升高,破损皮肤+BDSJS120mg/kg组大鼠的尿NAG. RBP含量有升高趋势,但未见显著性差异。
与溃疡皮肤组比较,溃疡皮肤+BDSJS240及溃疡皮肤+BDSJS120mg/kg组大鼠的尿NAG、RBP含量均见明显升高。
与相同给药剂量的破损皮肤组大鼠比较,疮疡皮肤模型大鼠给予BDSJS240mg/kg与120mg/kg,大鼠的肾脏系数、尿RBP含量均明显升高,肾组织病理学检查见肾小管扩张及上皮细胞出现肿胀、脱落或呈空泡变等明显病变。
结论
相同给药剂量下,BDSJS对疮疡皮肤大鼠的肾毒性高于其对破损皮肤大鼠的肾毒性。提示,临床应用含汞制剂应高度重视创面深度对药物吸收和汞蓄积的影响。
2炉甘石对BDSJS中汞成分毒性的影响
2.1炉甘石对红粉所致破损皮肤大鼠肾毒性的影响
目的
探讨炉甘石对破损皮肤大鼠汞染毒所致肾损伤有无保护作用。
方法
采用破损皮肤大鼠模型,以BDSJS的红粉作为汞染毒药物,以肾脏系数、尿NAG、 RBP含量及肾病理组织形态学为毒性评价指标,探讨炉甘石对汞引起的肾毒性是否具有减毒作用。
结果
与破损皮肤对照组比较,连续给药2周,红粉24mg/kg(累计剂量336mg/kg)剂量组大鼠的肾脏系数和尿NAG、RBP含量明显升高；等剂量炉甘石组大鼠的肾脏系数、尿NAG、RBP含量均无明显改变；红粉+炉甘石组大鼠的肾脏系数及尿NAG含量明显升高,RBP含量有升高趋势；与等剂量的红粉组比较,红粉+炉甘石组大鼠的肾脏系数有降低趋势。
与破损皮肤对照组比较,给药1周,红粉20mg/kg(累计剂量140mg/kg)可导致大鼠的肾脏系数明显升高,尿NAG有升高趋势,红粉+炉甘石组大鼠的肾脏系数明显升高,尿NAG含量有下降趋势。与等剂量的红粉组比较,红粉+炉甘石组大鼠肾脏系数有降低趋势,NAG含量明显下降。
结论：炉甘石对汞具有一定的减毒作用,但其减毒作用与汞的用量及使用周期有关。
2.2炉甘石对汞代谢的影响
目的
探讨炉甘石对汞代谢的影响及其机制。
方法
以破损皮肤大鼠为模型,以BDSJS中的红粉为汞染毒药物,测定血汞、尿汞、肾汞含量,采用颈动脉插管技术,观察不同时间点血汞浓度的变化,同时采用超滤法测定血浆蛋白结合率,以探讨炉甘石对血汞吸收、肾汞蓄积、尿汞排泄的影响及其机制；以GSH、MDA、T-SOD、Cu-ZnSOD及ATP含量为指标,观察炉甘石对破损皮肤大鼠汞染毒大鼠自由基代谢的影响。
结果
血、尿、肾组织的汞含量：红粉24mg/kg连续用药2周(累计剂量336mg/kg)及20mg/kg用药1周(累计剂量140mg),可造成破损皮肤大鼠血汞、尿汞及肾汞含量升高；红粉累计剂量336mg/kg时,等剂量的炉甘石对红粉组大鼠的血汞、尿汞、肾汞含量无明显影响；红粉累积剂量为140mg/kg时,等剂量的炉甘石可使红粉组大鼠血汞含量下降,尿汞、肾汞含量有升高趋势。
不同时间点炉甘石对血汞浓度的影响：单次给药后,红粉组及红粉+炉甘石组大鼠的血汞浓度逐渐增加,红粉组大鼠去药8h血汞浓度达到最高值；炉甘石组大鼠去药4h血汞达到最高值,此后血汞水平逐渐下降。
血浆蛋白结合率：在大鼠及正常人血浆中,与汞25ng/L组比较,汞25ng/L+锌组的血浆蛋白结合率有下降趋势；在人血清白蛋白(HSA)中,与汞25ng/L组比较,汞25ng/L+锌组的血浆蛋白的结合率明显下降。提示,在低剂量范围内,锌可能通过与汞竞争结合白蛋白,降低汞的血浆蛋白结合率。
对自由基代谢的影响：与破损皮肤对照组比较,红粉20mg/kg组大鼠肾组织的MDA水平和Na+K+-ATPase活力水平明显升高,SOD、GSH水平未见明显改变；与红粉组比较,红粉+炉甘石组大鼠的肾组织MDA水平和Na+K+-ATPase活力水平明显下降,T-SOD及Cu-ZnSOD水平有升高趋势,GSH无明显改变。
结论
炉甘石对汞具有一定的减毒作用,其机制可能是通过竞争机制降低汞与血浆白蛋白的结合,从而降低血汞浓度,加速尿汞排泄；同时锌还可通过降低汞引起大鼠肾组织MDA含量、提高SOD含量,参与自由基的代谢,保护肾组织的氧化损伤而发挥减毒作用。
2.2锌对肾小管上皮细胞汞毒性损伤的影响
目的
从体外角度探讨锌对人近端肾小管上皮细胞(HK-2)汞毒性损伤的作用及其机制。
方法
以氯化汞(HgCl2)及氯化锌(ZnCl2)作为汞离子和锌离子的供体,采用MTT及LDH释放率法筛选HgCl2和ZnCl2的作用浓度,并以此为基础借助高内涵成像分析技术,以细胞数、DNA含量、线粒体膜电位及细胞膜通透性为指标,探讨不同剂量的锌对汞染毒HK-2细胞的毒性作用。
结果
与对照组细胞比较,HgCl210、20、30μmol/L能够明显降低细胞数、增加DNA含量、线粒体膜电位、细胞膜通透性,并具有剂量依赖性；HgCl20.0μmol/L可导致HK-2细胞的膜电位明显升高,对DNA含量、细胞数及通透性均无明显影响;ZnCl20.1μmol/L对HK-2细胞的细胞数、DNA含量、线粒体膜电位及通透性均无明显影响。
与对照组细胞比较,ZnCl210、20μmol/L能够明显抑制HgCl210、20μmol/L引起的DNA含量的异常增高,增强细胞线粒体膜电位及通透性的增高；HgCl20.01μmol/L+ZnCl20.1μmol/L可致细胞数明显下降,细胞线粒体膜电位和膜通透性明显升高。
结论
HgCl2可造成HK-2细胞损伤；一定剂量的ZnCl2能够拮抗HgCl2引起的细胞DNA含量升高,但同时可造成细胞膜通透性及线粒体膜电位的升高。因此,在细胞水平,ZnCl2可能对HgCl2不具有直接减毒作用。
Badu Shengji San (BDSJS) as one of external preparations containing mercury,which has been used for thousands of years in TCM (tradational Chinese medicine) has a unique curative effect on the treatment of chronic refractory skin ulcer. However,mercury is an extremly toxic metal and can accumulate in human bodies,which has potential danger in clinical application. It is significant to research the accumulation and alleviation of the toxicity of mercury of BDSJS as a typical external preparations containing mercury for clinical safe utilization.
Our previous studies had proved that mercury was the main toxic component of BDSJS and kidney was its toxic target organ,however,compatible herbs could reduce the toxicity of mercury. Calamine which is another major component of BDSJS is made of zinc oxide and zinc can reduce blood mercury content and protect renal injury induced by mercury in recent study. Therefore, we hypothesized that calamine may be the most important mineral drug that may attenuate the toxicity of mercury. So the aim of this article was to clarify the accumulation characteristics of mercury of BDSJS and to expound the effects and mechanisms of calamine on the toxicity of mercury.
To clarify the accumulation characteristics of mercury in BDSJS, damaged-skin rats were treated with BDSJS0,25,50,100mg/kg/d for4weeks. Rats were sacrificed after the last dose, recovery4weeks and recovery8weeks respectively. The consentration of mercury in blood,urine and renal cortex, coefficient of kidney and pathological changes,urinary NAG and β2-MG, biochemical indexes of hepatic and renal function were detected.Our results showed that administration of BDSJS for4weeks could cause the accumulation of mercury in blood and mainly in kidney; blood and urinary mercury recovered after suspended for4weeks and8weeks respectively; more than70%mercury were removed in renal after8weeks; BDSJS100mg/kg could damage renal tubule, but it was reversible and could recover after suspended for4weeks.We had found that BDSJS50mg/kg was a safe dose for rats.
According to the result above,we calculated the dose range of human beings and evaluated the accumulation and toxicity of mercury of patients suffered from chronic skin ulcer who were treated with BDSJS for4weeks. The concentration of mercury in blood,urine,urinary NAG and β2-MG, biochemical of hepatic and renal function were detected after the last dose, recovery2weeks and recovery6weeks respectively. Our results showed that treatment of BDSJS for4weeks, blood mercury concentration revealed a rising trend, urine mercury concentration increased obviously;serum ALT,AST, BUN,Cr,urinary β2-MG had no obvious changes; the concentration of NAG in urine increased obviously; after suspended for6weeks, the concentration of mercury and NAG recovered to normal in urine.
We also compared the difference of nephrotoxicity induced by BDSJS between ulcerous and damaged-skin rats which were two different skin conditon models. We took the pathological kidney coefficient, urine RBP and NAG and renal pathological changes as indexes. Our results showed that,with the same dose, renal toxicity of BDSJS on ulcer-skin rats were worse than that on the damaged-skin rats,which suggested that doctors should pay attention to the difference of absorption and accumulation of mercury according to different wounds depth.
To expound the effects and mechanisms of calamine on the toxicity of mercury, several experiments in vivo and in vitro were carried out.
In vivo experiments, skin-damaged rats were respectively treated with hydrargyri oxydum rubrum,which is a herb of BDSJS containg mercury and hydrargyri oxydum rubrum added calamine.After the last dose, rats were sacrificed, the concentration of mercruy in kidney, blood and urine, urinary NAG and RBP and renal MDA、T-SOD、CuZn-SOD and GSH were measured.We also observed the activities of ATPase. The result showed that after administration of hydrargyri oxydum rubrum20mg/kg/d for1week, equivalent calamine had a partial protective effect on renal toxicity and could reduce the blood mercury concentration and increase urinary excretion of mercury and decrease MDA level significantly,compared with the rats in hydrargyri oxydum rubrum group. We also observed the effect of equivalent calamine on mercury concentration of blood at different time in damaged-skin rat in single does adminstration of hydrargyri oxydum rubrum. The results showed that blood mercury concentration in rats of hydrargyri oxydum rubrum and hydrargyri oxydum rubrum added calamine groups increased gradually after the treatment,and after withdrawal drug8hous and4hours reached the hightest respectively.
In order to clarify the mechanism that calamine decresed the mercury concentration in bood, plasma protein binding rates by ultrafiltration were carried out. The results showed that compared with25ng/L mercury group, protein binding rate in25ng/L Hg+Zn group had a decreased trend in plasma of rat and human plasmas; but the protein binding rate in mercury(25ng/L)+zinc group decreased obviously in human serum albumin. So, the plasma protein binding rate of mercury would decrease as a rusult of the competition of zinc.
In vitro experiments, we explored the effect of zinc ion on the toxicity of mercury by cultivating the human renal proximal tubular epithelial cells (HK-2), with the changes of mitochondrial membrane potential, DNA content, nucleus area, cell membrane permeability and cell number by Cellomics High Content Imaging Analysis (HCS) method.Our results showed that, comprared with the same dose of mercury, the combination of zinc and mercury could significantly inhibit the increase of DNA content,and increase the level of mitochondrial membrane potential and cell membrane permeability.So,zinc may have no protective effect on the toxicity of mercury to HK-2cells.
In conclusion, calamine can alleviate the toxicity of mercury to some extent, the mechanism may be related to decreasing the concentration of blood by competing with mercury in binding to serum albumin, accelerating the excretion of mercury in urine and zinc can also protect renal damage induced by oxidative stress of mercury by reducing the content of MDA and increasing the level of SOD in renal tissue.
国外最新研究发现ZnCl2对HgCl2引起的乳鼠肾损伤具有保护作用。提示,锌对汞诱发的肾损伤具有一定的保护作用。本课题前期研究已证明汞是BDSJS的主要毒性成分,肾脏是其主要毒性靶器官,且方中的配伍药味能够减轻汞所致的肾损伤。在配伍药味中,炉甘石(煅)的主要成分是氧化锌。由此我们在前期研究基础上进行推论,认为以锌为主要成分的炉甘石可能是BDSJS中汞成分的减毒药味。基于以上认识,本研究以含汞成分的红粉作为染毒药物,观察炉甘石对破损皮肤大鼠肾损伤的影响,探讨其对汞代谢方面的可能影响及其机制。目前,国内对炉甘石及锌降低汞毒性及其配伍减毒机制尚无报道。
本论文包括两个部分：BDSJS的毒性特点和方中炉甘石对汞毒性的影响。
1BDSJS的毒性特点研究
1.1对破损皮肤大鼠反复给药汞成分在体内的蓄积情况研究
目的
观察BDSJS反复给药后汞成分在大鼠体内的蓄积情况,明确BDSJS的安全剂量、用药周期及毒性可逆程度。
方法
采用破损皮肤大鼠模型,分别以高、中、低剂量的100、50、25mg/kg BDSJS涂敷于大鼠背部破损皮肤给药区,敷药后固定24h,每日给药1次,连续给药4周。检测给药4周、停药4周及停药8周大鼠血、尿、肾皮质中的汞含量,观察汞成分在破损皮肤大鼠体内的蓄积情况,并以肾早期损伤指标尿视黄醇结合蛋白(RBP)、N-乙酰-p-D-氨基葡萄糖苷酶(NAG)和β2-微球蛋白(β2-MG)含量、肝肾功能、凝血时间及肾组织形态学变化为肾毒性指标,评价汞蓄积是否可造成肾组织的损伤及其严重程度。
结果
与破损皮肤对照组比较,用药4周BDSJS高、中、低剂量组大鼠的血汞、尿汞、肾汞含量均明显升高,且升高呈剂量依赖性；停药4周,BDSJS各组大鼠的血汞含量均已恢复至正常水平,尿汞含量下降80-90%,肾汞含量下降50%以上；停药8周, BDSJS各组大鼠尿汞均恢复至正常水平,肾汞下降70%以上,但仍有一定蓄积。
BDSJS高剂量组给药4周,在肾汞含量为(47.99±15.66)ng/g,血汞含量为(72.06±18.03)ng/g,尿汞含量为(1278.84±711.82)ng/mL时,大鼠出现肾脏系数和β2-MG含量的明显升高,肾组织病理检查见少数大鼠出现肾小管上皮细胞肿胀；停药4周,肾汞含量为(20.43±5.09)ng/g,尿汞含量为(82.70±25.83)ng/mL,血汞含量为(5.59±0.94)ng/mL(基本恢复正常水平)时,肾脏系数、尿P2-MG及肾组织形态基本恢复正常；停药8周,虽肾组织中汞仍有一定蓄积,含量为(18.60±12.35)ng/g,但尿β2-MG及肾组织形态恢复正常。中、低剂量组大鼠在给药4周,血汞分别为(38.44±28.72)ng/g和(26.63±18.67)ng/g,尿汞分别为(380.80±119.32) ng/mL和(239.53±110.34)ng/mL,肾汞含量分别为(31.27±11.21)μg/g和(11.93±3.12)μg/g,但肾脏系数及尿P2-MG未见明显差异。
结论
BDSJS连续外敷4周,可造成汞在破损皮肤大鼠血液及肾脏中的蓄积,主要蓄积在肾脏；血中汞的清除较快,停药4周基本恢复到正常水平；停药8周,BDSJS中、低剂量组大鼠尿汞恢复至正常水平,肾脏中汞的清除超过70%,但仍有一定蓄积；BDSJS高剂量100mg/kg可造成肾小管的轻度损伤,但其损伤是可逆的,停药4周后可基本恢复,中剂量50mg/kg为其安全剂量。
1.2BDSJS对慢性皮肤溃疡患者汞成分在机体内的蓄积情况研究
目的
采用动物安全性评价得出的安全剂量和用药周期,观察慢性下肢疮疡患者以BDSJS外敷治疗4周及停药后汞在体内的蓄积情况,为制定临床安全剂量和给药周期提供依据。
方法
入组患者每日给药1次,或视患者创面情况隔日换药1次,以0.28mg/cm2/d的剂量治疗4周,测定患者治疗前、治疗4周、停药2周及停药6周的血汞及尿汞含量,并以血清ALT、AST、BUN、Cr、尿NAG及β2-MG为毒性观察指标,评价汞蓄积对患者肝、肾功能指标的影响。
结果
外敷BDSJS治疗慢性皮肤溃疡,患者在用药4周血汞含量为(8.10±14.81)ng/mL,尿汞含量为(11.51±17.75)ng/mL,与治疗前比较,血汞含量有升高趋势,尿汞含量明显升高；停药2周和停药6周,患者血汞及尿汞含量未见明显升高。
与治疗前比较,治疗4周、停药2周及停药6周,血清中ALT、AST、BUN、Cr及尿β2-MG含量未见明显升高；治疗4周,患者尿NAG含量明显升高,停药2周,尿NAG含量有升高趋势,停药6周,尿NAG含量未见明显升高。
结论
慢性难愈性下肢溃疡患者20例,患处外敷BDSJS,以0.28mg/cm2/d剂量用药4周,在患者尿中检测到汞含量明显升高,血汞含量有升高趋势；停药6周,患者血汞及尿汞基本恢复至正常水平。但治疗期及停药期BDSJS均未造成肝肾功能的明显异常,提示,汞在机体内短时间蓄积(血汞含量低于8.1ng/mL,尿汞低于含量11.5ng/mL)不会导致肾损伤。该研究结果进一步证实,动物安全性实验得出的安全剂量和周期对临床用药具有指导作用。
1.3对不同皮肤损伤条件大鼠的肾毒性差异
目的
比较BDSJS对不同皮肤损伤条件大鼠的肾毒性差异。
方法
采用BDSJS的毒性剂量,以肾脏系数、尿RBP、NAG含量及肾组织的病理形态为肾毒性观察指标,比较其对破损皮肤和疮疡皮肤两种不同皮肤损伤条件大鼠的肾毒性差异。
结果
与破损皮肤对照组比较,破损皮肤+BDSJS240mg/kg组大鼠的尿NAG、RBP含量明显升高,破损皮肤+BDSJS120mg/kg组大鼠的尿NAG. RBP含量有升高趋势,但未见显著性差异。
与溃疡皮肤组比较,溃疡皮肤+BDSJS240及溃疡皮肤+BDSJS120mg/kg组大鼠的尿NAG、RBP含量均见明显升高。
与相同给药剂量的破损皮肤组大鼠比较,疮疡皮肤模型大鼠给予BDSJS240mg/kg与120mg/kg,大鼠的肾脏系数、尿RBP含量均明显升高,肾组织病理学检查见肾小管扩张及上皮细胞出现肿胀、脱落或呈空泡变等明显病变。
结论
相同给药剂量下,BDSJS对疮疡皮肤大鼠的肾毒性高于其对破损皮肤大鼠的肾毒性。提示,临床应用含汞制剂应高度重视创面深度对药物吸收和汞蓄积的影响。
2炉甘石对BDSJS中汞成分毒性的影响
2.1炉甘石对红粉所致破损皮肤大鼠肾毒性的影响
目的
探讨炉甘石对破损皮肤大鼠汞染毒所致肾损伤有无保护作用。
方法
采用破损皮肤大鼠模型,以BDSJS的红粉作为汞染毒药物,以肾脏系数、尿NAG、 RBP含量及肾病理组织形态学为毒性评价指标,探讨炉甘石对汞引起的肾毒性是否具有减毒作用。
结果
与破损皮肤对照组比较,连续给药2周,红粉24mg/kg(累计剂量336mg/kg)剂量组大鼠的肾脏系数和尿NAG、RBP含量明显升高；等剂量炉甘石组大鼠的肾脏系数、尿NAG、RBP含量均无明显改变；红粉+炉甘石组大鼠的肾脏系数及尿NAG含量明显升高,RBP含量有升高趋势；与等剂量的红粉组比较,红粉+炉甘石组大鼠的肾脏系数有降低趋势。
与破损皮肤对照组比较,给药1周,红粉20mg/kg(累计剂量140mg/kg)可导致大鼠的肾脏系数明显升高,尿NAG有升高趋势,红粉+炉甘石组大鼠的肾脏系数明显升高,尿NAG含量有下降趋势。与等剂量的红粉组比较,红粉+炉甘石组大鼠肾脏系数有降低趋势,NAG含量明显下降。
结论：炉甘石对汞具有一定的减毒作用,但其减毒作用与汞的用量及使用周期有关。
2.2炉甘石对汞代谢的影响
目的
探讨炉甘石对汞代谢的影响及其机制。
方法
以破损皮肤大鼠为模型,以BDSJS中的红粉为汞染毒药物,测定血汞、尿汞、肾汞含量,采用颈动脉插管技术,观察不同时间点血汞浓度的变化,同时采用超滤法测定血浆蛋白结合率,以探讨炉甘石对血汞吸收、肾汞蓄积、尿汞排泄的影响及其机制；以GSH、MDA、T-SOD、Cu-ZnSOD及ATP含量为指标,观察炉甘石对破损皮肤大鼠汞染毒大鼠自由基代谢的影响。
结果
血、尿、肾组织的汞含量：红粉24mg/kg连续用药2周(累计剂量336mg/kg)及20mg/kg用药1周(累计剂量140mg),可造成破损皮肤大鼠血汞、尿汞及肾汞含量升高；红粉累计剂量336mg/kg时,等剂量的炉甘石对红粉组大鼠的血汞、尿汞、肾汞含量无明显影响；红粉累积剂量为140mg/kg时,等剂量的炉甘石可使红粉组大鼠血汞含量下降,尿汞、肾汞含量有升高趋势。
不同时间点炉甘石对血汞浓度的影响：单次给药后,红粉组及红粉+炉甘石组大鼠的血汞浓度逐渐增加,红粉组大鼠去药8h血汞浓度达到最高值；炉甘石组大鼠去药4h血汞达到最高值,此后血汞水平逐渐下降。
血浆蛋白结合率：在大鼠及正常人血浆中,与汞25ng/L组比较,汞25ng/L+锌组的血浆蛋白结合率有下降趋势；在人血清白蛋白(HSA)中,与汞25ng/L组比较,汞25ng/L+锌组的血浆蛋白的结合率明显下降。提示,在低剂量范围内,锌可能通过与汞竞争结合白蛋白,降低汞的血浆蛋白结合率。
对自由基代谢的影响：与破损皮肤对照组比较,红粉20mg/kg组大鼠肾组织的MDA水平和Na+K+-ATPase活力水平明显升高,SOD、GSH水平未见明显改变；与红粉组比较,红粉+炉甘石组大鼠的肾组织MDA水平和Na+K+-ATPase活力水平明显下降,T-SOD及Cu-ZnSOD水平有升高趋势,GSH无明显改变。
结论
炉甘石对汞具有一定的减毒作用,其机制可能是通过竞争机制降低汞与血浆白蛋白的结合,从而降低血汞浓度,加速尿汞排泄；同时锌还可通过降低汞引起大鼠肾组织MDA含量、提高SOD含量,参与自由基的代谢,保护肾组织的氧化损伤而发挥减毒作用。
2.2锌对肾小管上皮细胞汞毒性损伤的影响
目的
从体外角度探讨锌对人近端肾小管上皮细胞(HK-2)汞毒性损伤的作用及其机制。
方法
以氯化汞(HgCl2)及氯化锌(ZnCl2)作为汞离子和锌离子的供体,采用MTT及LDH释放率法筛选HgCl2和ZnCl2的作用浓度,并以此为基础借助高内涵成像分析技术,以细胞数、DNA含量、线粒体膜电位及细胞膜通透性为指标,探讨不同剂量的锌对汞染毒HK-2细胞的毒性作用。
结果
与对照组细胞比较,HgCl210、20、30μmol/L能够明显降低细胞数、增加DNA含量、线粒体膜电位、细胞膜通透性,并具有剂量依赖性；HgCl20.0μmol/L可导致HK-2细胞的膜电位明显升高,对DNA含量、细胞数及通透性均无明显影响;ZnCl20.1μmol/L对HK-2细胞的细胞数、DNA含量、线粒体膜电位及通透性均无明显影响。
与对照组细胞比较,ZnCl210、20μmol/L能够明显抑制HgCl210、20μmol/L引起的DNA含量的异常增高,增强细胞线粒体膜电位及通透性的增高；HgCl20.01μmol/L+ZnCl20.1μmol/L可致细胞数明显下降,细胞线粒体膜电位和膜通透性明显升高。
结论
HgCl2可造成HK-2细胞损伤；一定剂量的ZnCl2能够拮抗HgCl2引起的细胞DNA含量升高,但同时可造成细胞膜通透性及线粒体膜电位的升高。因此,在细胞水平,ZnCl2可能对HgCl2不具有直接减毒作用。
Badu Shengji San (BDSJS) as one of external preparations containing mercury,which has been used for thousands of years in TCM (tradational Chinese medicine) has a unique curative effect on the treatment of chronic refractory skin ulcer. However,mercury is an extremly toxic metal and can accumulate in human bodies,which has potential danger in clinical application. It is significant to research the accumulation and alleviation of the toxicity of mercury of BDSJS as a typical external preparations containing mercury for clinical safe utilization.
Our previous studies had proved that mercury was the main toxic component of BDSJS and kidney was its toxic target organ,however,compatible herbs could reduce the toxicity of mercury. Calamine which is another major component of BDSJS is made of zinc oxide and zinc can reduce blood mercury content and protect renal injury induced by mercury in recent study. Therefore, we hypothesized that calamine may be the most important mineral drug that may attenuate the toxicity of mercury. So the aim of this article was to clarify the accumulation characteristics of mercury of BDSJS and to expound the effects and mechanisms of calamine on the toxicity of mercury.
To clarify the accumulation characteristics of mercury in BDSJS, damaged-skin rats were treated with BDSJS0,25,50,100mg/kg/d for4weeks. Rats were sacrificed after the last dose, recovery4weeks and recovery8weeks respectively. The consentration of mercury in blood,urine and renal cortex, coefficient of kidney and pathological changes,urinary NAG and β2-MG, biochemical indexes of hepatic and renal function were detected.Our results showed that administration of BDSJS for4weeks could cause the accumulation of mercury in blood and mainly in kidney; blood and urinary mercury recovered after suspended for4weeks and8weeks respectively; more than70%mercury were removed in renal after8weeks; BDSJS100mg/kg could damage renal tubule, but it was reversible and could recover after suspended for4weeks.We had found that BDSJS50mg/kg was a safe dose for rats.
According to the result above,we calculated the dose range of human beings and evaluated the accumulation and toxicity of mercury of patients suffered from chronic skin ulcer who were treated with BDSJS for4weeks. The concentration of mercury in blood,urine,urinary NAG and β2-MG, biochemical of hepatic and renal function were detected after the last dose, recovery2weeks and recovery6weeks respectively. Our results showed that treatment of BDSJS for4weeks, blood mercury concentration revealed a rising trend, urine mercury concentration increased obviously;serum ALT,AST, BUN,Cr,urinary β2-MG had no obvious changes; the concentration of NAG in urine increased obviously; after suspended for6weeks, the concentration of mercury and NAG recovered to normal in urine.
We also compared the difference of nephrotoxicity induced by BDSJS between ulcerous and damaged-skin rats which were two different skin conditon models. We took the pathological kidney coefficient, urine RBP and NAG and renal pathological changes as indexes. Our results showed that,with the same dose, renal toxicity of BDSJS on ulcer-skin rats were worse than that on the damaged-skin rats,which suggested that doctors should pay attention to the difference of absorption and accumulation of mercury according to different wounds depth.
To expound the effects and mechanisms of calamine on the toxicity of mercury, several experiments in vivo and in vitro were carried out.
In vivo experiments, skin-damaged rats were respectively treated with hydrargyri oxydum rubrum,which is a herb of BDSJS containg mercury and hydrargyri oxydum rubrum added calamine.After the last dose, rats were sacrificed, the concentration of mercruy in kidney, blood and urine, urinary NAG and RBP and renal MDA、T-SOD、CuZn-SOD and GSH were measured.We also observed the activities of ATPase. The result showed that after administration of hydrargyri oxydum rubrum20mg/kg/d for1week, equivalent calamine had a partial protective effect on renal toxicity and could reduce the blood mercury concentration and increase urinary excretion of mercury and decrease MDA level significantly,compared with the rats in hydrargyri oxydum rubrum group. We also observed the effect of equivalent calamine on mercury concentration of blood at different time in damaged-skin rat in single does adminstration of hydrargyri oxydum rubrum. The results showed that blood mercury concentration in rats of hydrargyri oxydum rubrum and hydrargyri oxydum rubrum added calamine groups increased gradually after the treatment,and after withdrawal drug8hous and4hours reached the hightest respectively.
In order to clarify the mechanism that calamine decresed the mercury concentration in bood, plasma protein binding rates by ultrafiltration were carried out. The results showed that compared with25ng/L mercury group, protein binding rate in25ng/L Hg+Zn group had a decreased trend in plasma of rat and human plasmas; but the protein binding rate in mercury(25ng/L)+zinc group decreased obviously in human serum albumin. So, the plasma protein binding rate of mercury would decrease as a rusult of the competition of zinc.
In vitro experiments, we explored the effect of zinc ion on the toxicity of mercury by cultivating the human renal proximal tubular epithelial cells (HK-2), with the changes of mitochondrial membrane potential, DNA content, nucleus area, cell membrane permeability and cell number by Cellomics High Content Imaging Analysis (HCS) method.Our results showed that, comprared with the same dose of mercury, the combination of zinc and mercury could significantly inhibit the increase of DNA content,and increase the level of mitochondrial membrane potential and cell membrane permeability.So,zinc may have no protective effect on the toxicity of mercury to HK-2cells.
In conclusion, calamine can alleviate the toxicity of mercury to some extent, the mechanism may be related to decreasing the concentration of blood by competing with mercury in binding to serum albumin, accelerating the excretion of mercury in urine and zinc can also protect renal damage induced by oxidative stress of mercury by reducing the content of MDA and increasing the level of SOD in renal tissue.
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